Steroid containing difluoroamino and fluoroimino groups



United States Patent 3,196,167 STEROID CONTAJNING DIFLUOROAMINQ ANDFLUOROIMINO GROUPS Anesfis L. Logothetis, Wilmington, DeL, assignor toE. I. du Pont de Nemours and Company, Wilmington, DeL, a corporation ofDelaware No Drawing. Filed Aug. 5, 1963, Ser. No. 300,109 14 Claims.(Ci. zen-397.2

This invention relates to new steroids and to a method of preparingthese compounds. More specifically, the invention concerns new steroidsbearing difluoroamino or fluoroimino substituents on adjacent carbonatoms and to their preparation.

It has been found that the properties of steroid compounds can bealtered by placing substituents on the steroid nucleus; thus, a greatamount of research has been directed to the synthesis of steroidcompounds. No work has been reported, however, in the area ofdifiuoroamino and fiuoroimino substituted steroids.

The new products of this invention are steroids having on each of thetwo adjacent annular carbon atoms in the (4,5) or (5,6) positions adifluoroamino, NF and a fluoroimino, =NF, substituent.

These compounds are prepared by the following oneor two-step process:

(a) Reacting dinitrogen tetrafluoride under essentially anhydrousconditions with a steroid containing an intracyclic carbon-to-carbondouble bond, between the 4- and S-carbons or the 5- and G-carbons,whereby a 4,5- or 5,6-bis(difluoroamino) steroid is formed in accordancewith the following simplified equation in which only the reactiveportion of the molecule is shown:

(b) Dehydrofluor'ination of the bis(difluoroamino) steroid of step (a)may be accomplished by reacting it with .a hydrogen fluoride acceptor,whereby the difluoroamino groups which are attached to a carbon atomalso bearing a hydrogen atom, i.e., to either the 4- or the 6- carbonatom, is converted to a fluoroimino group with formation of a5adifluoroamino-4- or -fluoroimino steroid, in accordance with thesimplified equation:

in which any valences of the depicted carbons not bonded to hydrogen isbonded to annular carbon of the steroid molecule.

The difluoroamino and fiuoroimi-no steroids of this invention may, ofcourse, bear any of the other substituents commonly present in thesteroidal compounds. When these substituents are initially present inthe unsaturated steroid serving as starting material, they shouldobviously be those which are not appreciably reactive with dinitrogentetrafluoride, i.e., which are insuificiently reactive to prevent thedesired reaction from proceeding to a useful extent. Examples ofsuitable substituents (hydrogen is not herein considered a substituent),which may be attached either to annular carbons or to exocyclic carbons,include hydrocarbon radicals (preferably low alkyl groups) andfunctional groups such as hydroxy, ether (hydrocarbyloxy), oxo, acyloxy,carboxyl, ester (hydroice carbyloxycarbonyl), oxido, acetal,carbonamido, cyano, nitro and halogen. Sensitive functions such asamino, diallrylamino, intracyclic unsaturation or exocyclic unsaturation(ethylenic or acetylenic) can, however, be introduced by knovm methodsinto the difluoroamino or fluoroimino steroid after it has been formed.

For reasons of greater accessibility, the unsaturated steroids preferredas starting materials are those which contain a total of from 18 to 36carbon atoms.

In the first step of the process, the relative proportions of the tworeactants (unsaturated steroid and N F are not critical. For betterutilization of the steroid and greater ease of separation of thereaction product, the N 1 is generally used in at least molar equivalentwith respect to the steroid, and preferably in slight to moderate excessthereover.

The reaction is conveniently conducted in an essentially inert organicliquid medium which dissolves the steroid to at least some extent, e.g.,5% by weight. Suitable solvents include hydrocarbons such as heptane,petroleum ether, cyclohexane, benzene or toluene; halohydrocarbons suchas carbon tetrachloride, chloroform, l,2-dichlor0- ethane,1,1,Z-trichloro-l,2,2-trifluoroethane, hexafluoropropylene dimer,chlorobenzene; nitriles such as acetonitrile or benzonitrile; and thelike. The reaction medium should be aliphatically saturated, to avoidside-reactions with the N R, and excessive consumption of the latter,and substantially anhydrous, since N 1 is hydrolyzable.

The reaction proceeds at temperatures as low as about 25 C. but at tooslow a rate to be practical. It is therefore preferred to operate at atemperature of at least 50 (3., most usefully in the range of 50200 C.

Since N F is a gas boiling at about -73 C., the reaction is conducted insealed vessels, either at the autogenous pressure developed by thereactants and solvent at the operating temperature or under additionalexternal pressure, which may be any desired one, for example up to 5000atmospheres or higher. Use is made of a reaction vessel whose innersurface resists chemical attack by N F for example stainless steel, thecommercial nickel-ironrnolybdenum alloy known as Hastelloy C, orplatinum.

The resulting 4,5- or 5,6 bis(difluoroamino) steroid can be separated byany appropriate means, such as crystallization from a suitable solventor chromatographic methods. These bis(difiuoroamino) steroids arecrystalline solids which, in contrast to many compounds containing N-Fbonds, are perfectly stable and can be handled in complete safety.

In the optional second step of the process, the bis(difluoroamino)steroid is brought in intimate contact with a hydrogen fluoride acceptorunder conditions which favor dehydrofiuorination. Suitable hydrogenfluoride acceptors include the fluorides of alkali metals of atomicnumber 11-55 (soditun, potassium, rubidium and cesium fluorides); thecarbonates of the same metals, and alkali metal alkoxides such as sodiumor potassium methoxide or ethoxide. The hydrogen fluoride acceptor isadvantageously used in at least the calculated amount, that is, inamounts of at least one mole (preferably more) per NF group to beconverted.

The reaction is conducted in a liquid medium which dissolves the steroidand preferably, but not essentially, has also at least some solventpower for the hydrogen fluoride acceptor. The halohydrocarbons andnitriles already mentioned in connection with the first step aresuitable reaction media for this purpose, as are also ethers such asdioxane, tetrahydrofuran or 1,2-dimethoxyet-hane; sulfoxides such asdimethyl sulfoxide; amides such as dimethylformam-ide, and the like.While a small amount of Water can usually be tolerated, the reactionmedium is preferably substantially anhydrous.

The temperature of the dehydrofluorination reaction may be as low asabout 25 C., particularly when using a combination of solvent andhydrogen fluoride acceptor such that the latter is dissolved to anapreciable extent. Generally speaking, the preferred range oftemperature is that between 50 and 125 C., although higher temperatures,e.g., up to 200 C., can be used if desired.

The resulting reaction product can be separated and purified, ifnecessary, by crystallization or chromatographic methods.

These defluoroarnino fluoroimino steroids, like the bisdifluoroaminosteroids, are crystalline solids which can be handled in completesafety.

TheNF and/or :NF substituted steroids obtained either by process (a) orby process (a) plus process (b) can in turn be subjected to otherreactions (for example, hydrolysis, oxidation, esterification, etc.),using known procedures, in order to introduce other substituents or toreplace substituents already present by others.

The examples which follow illustrate some of these transformations.

In the following examples, the spatial configuration .(or or {3) of thedifiuoroamino group is not stated, since it is not known with certainty.Other substituents are designated as a or 5 whenever their configurationis known. 1

EXAMPLE 1 3/8-acetoxy-5,6bis(difluoroamino)cholestane A solution of g.(0.0236 mole) of cholesteryl acetate in 13 ml. of chloroform and 7 ml.of acetonitrile was placedin a collapsible platinum tube. The tube wascooled to -I96 C., evacuated and 5.0 g. (0.0458 mole) of dinitrogentetrafiuoride was condensed in it, after which the tube was heated at 70C. for 4 hours under 500 atm. external hydraulic pressure. Aftercooling, the tube was opened, excess N 11; was allowed to evaporate, thesolvent was removed under reduced pressure and the residue wascrystallized from ethanol to give 8.0 g. (63% yield) of3fi-acetoxy-5,6-bis(difluoroamino)cholestane as colorless crystals,IVLP. 129.5130 C.

Analysis.-Cald. for C29H43F4N202: C, H, 9.08; N, 5.26; F, 14.25. Found:C, 65.09; H, 9.17; N,

4 EXAMPLE 2 3,8-acet0xy-5-diflu0r0amino-o-fluoroiminocholestane OsF AcO-

A mixture of 4.0 g. (0.0075 mole) of 3B-acetoxy-5,6-bis(difluoroarnino)cholestane, 6.0 g. (0.045 mole) of cesium fluoride,50 ml. of chloroform and 50 ml. of acetonitriie was heated to reflux(about 70 C.) for 4 hours. The mixture was then filtered and thefiltrate was evaporated under reduced pressure to give a crystallineresidue which, after recrystallization from ethanol, gave 2.4 g. (62.5%yield) of 3fi-acetoxy-5-difluoroamino-6-fluoroiminocholestane ascolorless needles, M.P. 165-166 C.

Analysis.Calcd. for C H F N O C, 67.98; H, 9.24; N, 5.46; F, 11.15.Found: C, 67.91; H, 9.10; N, 5.45; F. 10.90.

The infrared spectrum (KBr) showed absorptions at 5.75 (acetate),6.10,u, (CzNF, weak), 10.25, 10.34, 10.55, 10.75, 10.85, 11.00 and 11.55(NF). The F nn-r spectrum also supported the assigned structure.

EXAMPLE 3 ch L A mixture of 5.0 g. of3fi-acetoxy-5,6-bis(difluoroamino)cholestane, ml. of methanol and 30 ml.of concentrated hydrochloric acid was stirred at 40 C. for

18 hours, then heated to reflux, and enough water was added to causeslight cloudiness. The precipitate which formed on cooling was collectedby filtration. There was obtained 4.5 g. (95% yield) of5,6-bis(difluoroamino)- cholestane-3fi-ol as colorless crystals, MP.127128 C.

Analysis.Calcd. for C H F N O: C, 66. 10; H, 9.45; N, 5.72; F, 15.50.Found: C, 65.89; H, 9.72; N, 5.44; F, 1369.

The assigned structure was further supported by the F n-m-r spectrum andthe infrared spectrum, the latter showing absorption (Nujol mull) at2.98 (OH).

EXAMPLE 4 MeOH/H Cl NF; NF

A solution of 5.0 g. of 3,B-acetoxy-S-difiuoroamino-6-fiuoroiminocholestane, 200 ml. of methanol, 10 ml. of chloroform and 30m1. of cencentrated hydrochloric acid was stirred at room temperaturefor 18 hours. On dilution with water, extraction of the organic productwith chloroform and evaporation of the solvent an oily residue wasobtained which, on crystallization from ethanol, gave 3.5 g. (76% yield)of -difiuoroamino-6-fiuoroiminocholestane-Efi-ol as colorless crystals,MP. 131132 C.

Analysis.Calcd. for C d-1 1 14 0: C, 68.90; H, 9.64; N, 5.95; F, 12.13.F, 11.28.

The infrared spectrum (KBr) showed absorptions at 2.92 1 (OH), 6.09 1.(CzNF, weak), 11.58 and 1233 (NF), and the F n-rn-r spectrum furthersupported the assigned structure.

The same compound was also obtained, although in poorer yield, bydehydrofluorinating 5,6-bis(difiuoroamino)cholestane-3B-ol with cesiumfluoride in refluxing acetonitrile/chloroform by the procedure ofExample 2.

EXAMPLE 5 S-difluoroam in0-6-fluoroiminocholestane-3-0rze NF: NF NF: NF

Found: C, 68.09; H, 9.76; N, 5.91; I

To a stirred solution of 2.7 g. (0.00575 mole) of 5-difluoroamino-6-fluoroiminocholestane-3,8-ol in ml. of acetone wasslowly added an excess of Jones reagent (solution of 10.3 g. of chromiumtrioxide in 30 ml. of water and 3.7 ml. of concentrated sulfuric acid;see Bowden, Heil-bron, Jones and Weedon, J. Chem. Soc. 1946, 39). Themixture was stirred for one-half hour, after which the chromium saltswere removed by filtration. The filtrate was diluted with water,extracted with petroleum ether and the petroleum ether was evaporatedunder reduced pressure to give a residual oil which, aftercrystallization from ethanol-water, gave 1.6 g. yield) of5-difiuoroarnino-6-fluoroiminocholestatic-3-one as colorless crystals,M.P. 11-0-111 C.

Analysis.-Calcd. for C H F N O: C, 69.19; H, 9.25; N, 5.98; F, 12.17.Found: C, 68.92; H, 8.95; N, 5.75; F, 11.13.

The infnared spectrum (KBr) showed absorptions at 5.76,!1. (C O), 6.0(C=NF, weak), 11.45, 11.64 and 12.05p. (N-F), and the F n-rn-r spectrumalso supported the assigned structure.

EXAMPLE 6 5 ,6-b1's(di fluoroamino) cholestane-3-0ne CrOa N F: NF:NF2\NF2 A solution of 5.0 g. (0.01 mole) of5,6-bis(difluoroamino)cholestane-3B ol in 50 ml. of acetone was slowlytreated with an excess of Jones reagent. The mixture was stirred at roomtemperature for one hour, the chromium salts were removed by filtration,the filtrate was diluted with water and extracted with diethyl ether. Onevaporation of the ether under reduced pressure an oily residue wasobtained which, on crystallization from ethanol-water, gave 2.5 g. (50%yield) of 5,6-bis(difluoroamino) cho1estane-3-one as colorless crystals,M.P. 127- 128 C.

Analysis-Calm. for C H F N O: C, 66.39; H, 9.08; N, 5.73; P, 15.56.Found: C, 66.20; H, 8.84; N, 5.70; F, 14.81.

The assigned structure was supported by the F n-tn-r spectrum and by theinfrared spectrum (Nujol mull) showing absorptions at 5.80 1. (C=O),10.42, 10.55, 10.70, 11.50 and 1170 (NF).

The foregoing examples are to be considered as illustrative rather thanlimitative, since the described process is broadly applicable to thepreparation of steroids having a difluoroamino substituent on the5-carbon and either a di-fiuoroamino or a fluoroamino subst-ituent onone of the 4- or 6-carbons from any steroid having intr-acycliccarbon-to-carbon unsaturation between the 4- and 5- or the 5- and 6carbons.

From the stand-point of steroid classification, the products of greatestinterest in this invention are the bis(difluoroamino) anddifluoroamino-fluoroamino steroids (with the subs-tituents at thepreviously stated positions) of the following classes: estranes,androstanes, pregnanes, cholanes, 'cholestanes, ergostanes andstigmastanes.

Since the preferred starting materials are the intracyclicallyunsaturated steroids containing from 1 8 to 36 carbon atoms, thepreferred products of the invention ar correspondingly the bis(difiuoroarnino), and the difiuoro- ,amino-flu'oroimino steroids havingfrom 18 to 36 carbon atoms.

Additional specific examples of unsaturated steroids which can bereacted with dinitrogen tetrafluoroide in- 'clude those listed belowtogether with the resulting reaction products, the bis(difluoroamino)steroids, and their dehydrofluorination products, that is, thedifluoroaminoknown methods such as hydrolysis, oxidation,esterification, etherification, acetalizat ion and the like.

Starting Material Reaction Products AcO- CH (EHOAe17B-aeetoxy-3-ethy1enedioxy-5,fi-bis (difluoroamino)-androstane and 17B-acetoxy-3-ethy1enedioxy-5-difluoroamino-G-fluoroiminoandrostane.

3B,17B-d1aeetoxy-5,6-bis(difluoroamino)- B-norandrostane and36,17B-diacetoxy- 5-difluoroamino-G-fiuoroimino-B- norandrostane.

Starting Material Reaction Products G H; i) H O A c 14.35,20Bdiacetoxy-4,5-bis4difluoroamluo) pregnane and35,205-diaeetoxyA-fiuoroimino-5-difluoroaminopregnane.

1 AeO- i 15..-- 4,5-bis (difiuoroamino)-17B-hydroxyandrostene-3-one and4-fiuoroimino-5-difluoroamino-HB-hydroxyandrostene 3-one.

16... 4,5-bis(difluoroamino)-pregnene-3,20-di0 and4-fiu0roimlno-5-difluoroamin0pregnone-3,20-dlone.

Steriods modified by the introduction of difiuoroamino 2. A steroid ofclaim 1 wherein said grouping is and/ or iluoroimino groups possessunexpected and useful biological properties. Subcutaneous administrationof,

for example, 5,6-bis(fiuoroamino)cholestane-B-ol and 5-difluoroamino-6-fluoroiminocholestane-3-ol to young male 50 l ratscaused a marked inhibition of prostate gland growth without retardingbody growth or testicular development. A Stefold of claim 1 wherein Saidgrouping is This finding is unexpected since the cholesterol structurenormally lacks hormonal properties and discloses the use- 4 fulness ofthe products of the invention in the treatment 55 0 NF,

of androgen-dependent enlargements of the prostrate 'I gland.

As many apparently widely different embodiments of A Herold of claim 1wherein said grouping 13 this invention may be made without departingfrom the spirit and scope thereof, it is to be understood that this 0 6/invention is not limited to the specific embodiments there- NF: CH

of except as defined in the appended claims. u

The embodiments of the invention in which an exclusive property orprivilege is claimed are defined as follows: 5

1. A steroid selected from the class consisting of es- [\6/ tranes,androstanes, pregnanes, oholanes, cholestanes, ergostanes andstigmastanes wherein said steroids contains F as part of the polycyclicstructure a grouping selected P 3lgficetoxydfibis(difluomammo)cholestanefrom the class cmslstm'g 0 7.3,9-acetoxy-S-difluoroamin0-6-fiuoroiminocholestane.

E i I I 8. 5,6-bis(diflu oroam=ino)cholestane-one. 5c 50 05 c 9.5-difluoroamino-6-fluoroiminocholestane-3 3-01.

and 10. S-difluoroamino-6-fiuoroiminocholestane-3-one.

; t 2 F P 11. A process which comprises reacting dinitrogen tetra- NFINF NFI 5 fluoride with a steroid containing a double bond between carbonatoms selected from the position consisting of (4,5) and, (5,6) saidsteroid being selected from the class consisting of estranes,androstanes, pregnanes, cholanes, cholestanes, ergostanes andstigmastanes.

12. A process which comprises reacting a dehydrofluorinating agentselected from'the group consisting of alkali metal fluorides, alkalimetal carbonates, alkali metal methoxide and alkali metal ethoxide, witha steroid containing an NF group in the 5- position and an NF group in aposition selected from the class consisting of 4- and 6-, said steroidbeing selected from the class consisting of estranes, androstanes,pregnanes, cholanes, cholestanes, ergostanes and stigrnastanes, in amedium which dissolves the steroid.

13. The process of claim 11 wherein the steroid reactant is cholesterylacetate.

14. The process of claim 12 wherein the steroid reactant isSfi-acetoxy-iS-bis(difiuoroamino)cholestane, the dehydrofluorinatingagent is Cs? and the medium is a mixture of chloroform and acetonitrile.

No references cited.

LEWIS GOTTS, Primary Examiner.

1. A STEROID SELECTED FROM THE CLASS CONSISTING OF ESTRANES,ANDROSTANES, PREGNANES, CHOLANES, CHLOLESTANES, ERGOSTANES ANDSTIGMASTANES WHEREIN SAID STEROIDS CONTAINS AS PART OF THE POLYCYLICSTRUCTURE A GROUPING SELECTED FROM THE CLASS CONSISTING OF 6.3B-ACETOXY-5,6-BIS(DIFLUOROAMINO)CHOLESTANE.